The incidence of esophageal adenocarcinoma has been rising rapidly over the past two decades for unclear reasons. The most important risk factor for this cancer is Barrett's esophagus, a condition resulting from the reflux of gastric contents into the esophagus. In Barrett's esophagus the normal squamous cell lining of the esophagus is replaced by a specialized cell lining containing intestinal features. Risk factors associated with the development of Barrett's esophagus are not well defined. Furthermore, while men and women report symptoms of gastroesophageal reflux with equal frequency, men are twice as likely to develop Barrett's esophagus, suggesting gender-associated modifications of underlying risk factors. We propose to utilize the resources of three large, ongoing cohort studies, the Nurses' Health Study I, the Nurses' Health Study II, and the Health Professionals' Follow-up Study, to investigate inter-related mechanisms among both men and women that may contribute to Barrett's esophagus, including the roles of energy balance, insulin resistance, and chronic inflammation. All three cohorts provide prospectively collected data on potential risk factors for Barrett's esophagus, archived pre-diagnosis blood samples, and detailed endoscopy records and validated data on histologically-documented Barrett's esophagus. This unique investigative opportunity will allow us to examine, in detail, the associations between diet; gender; circulating levels of insulin, insulin derived growth factor, leptin, adiponectin, interleukin 6, tumor necrosis factor alpha, c-reactive protein, and other markers of insulin resistance and systemic inflammation; and other novel influences on the pathogenesis of Barrett's esophagus. PUBLIC HEALTH RELEVANCE: The goals of the project are to better understand reasons why people develop Barrett's esophagus, a condition that can lead to esophageal adenocarcinoma (a type of cancer whose frequency is rising faster than most other cancers). The project combines the resources of three large, ongoing cohort studies of both men and women to answer questions about why obesity is associated with Barrett's esophagus. These questions are especially relevant given our nation's current obesity epidemic.